This grant will initiate a research program to investigate the fundamental chemistry of recently discovered ionophore antibiotics. Aside from the general inhibitory activity against Gram-positive bacteria, ionophores generally exert a number of biological effects, many of unproven origin, which may result from their general ability to complex and transport cations, particularly calcium, as well as biogenic amines. Our efforts will be directed toward synthesis of the pseudomonic acids A and B, which display excellent activity against Gram-positive bacteria without exhibiting cross-resistance with other antibiotics. These substances are the simplest naturally-occurring ionophores yet discovered. The synthetic schemes offer optically pure antibiotics without an obligatory resolution, and careful studies will examine important chemistry of the heterocyclic, dihydro- and tetrahydropyran ring systems. The proposal is designed to explore and develop the fundamental chemistry of carbohydrate systems while working in the "unnatural" L-series. A convergent synthetic route has been designed which will conveniently allow preparation of interesting analogs. Our pseudomonic acid studies are directed toward challenging stereochemical aspects of these unique molecules including efforts to provide stereochemical control along an acyclic carbon backbone. This challenge is of general interest to antibiotic research, and our work involving Alpha-sulfinyl carbanion condensations will provide important contributions in this area.